Cellular immunity is mediated largely through T-cells which interact with foreign antigens presented in the context of classical MHC class I, class II and non-classical MHC molecules. The main goal is to understandthe structuralbasisfor T-cell recognition and T-cell signaling and the interplay with other key cellular antigen receptors in the innate immune system, such as Toll-like receptors (TLRs).Furthermore, the recent exciting discovery of an adaptive immune system in jawless vertebrates that uses Variable Lymphocyte Receptors(VLRs) with Leu-rich repeats,as in TLRs, for antigen recognition, but rearranges them as forTCRs and antibodies to create diversity,provides an important link for the evolution of antigen receptors in the immune system. Novelco-stimulatory receptors for op and 78 T-cell activation and differentiation will be pursued with Junctional Adhesion Molecule (JAML) for 78 T-cell activation and novel T-cell Ig and Mucin (TIM) receptors for Th1/Th2 commitment of CD4+ T-cells. The long term goal is to assemble a complete TCR signaling complex that includes the a|3TCR, pMHC, CDSy, 8, e,pound and CDS. The ap1,78 and pre-T-cell receptorsall recognize and interact with CDS, but their interactions differ as the components of the various TCR types are not conserved. The CDScomponents will be studied independently and as complexes with the different TCRs. In addition, the CDSco-receptor interaction will be investigated as TCR-pMHC-CDS complex. Many key questions will be addressed including the structuralprinciples of TCR/MHC recognition that define MHC restriction, what structural features are correlatedwith alloreactivity and autoimmunity, whether CDS interactswith both pMHC and TCR, and the major question concerning the structure, stoichiometry and function of the T-cell signaling complex.This later goal is ambitious ,but represents the only way to probe the structural basis of T-cell signaling. The benefits from this work include an increased understanding of the adaptive and innate immune response to microbial pathogens and elucidation of the structuralbasis of tolerance, autoimmunity, alloreactivity, cross-reactivity and host versus graft disease intransplantation.